The long term objective of both the proposal and the candidate is to more completely understand the relationship of malignancies and the host immune system so that increasingly effective immunotherapeutic strategies may be added to the armamentarium of cancer treatment. The candidate is an M.D., Ph.D. trained in immunology and hematopathology who is proposing a 5 year mentored research experience with Dr. Irving Weissman to expand research skills in murine systems, tumor immunology models, and molecular biology with the goal of preparing the applicant to establish an independent laboratory in an academic pathology department. Current efforts to induce immune responses to tumors in murine models suffer from two main difficulties. First, very aggressive, in vitro maintained tumor cell lines or transgenic mice that show simultaneous and early emergence of quickly growing tumors are used as a model for human malignancy. These may place unrealistic burdens on any anti-tumor immune responses induced in experimental animals. Second, it has been very difficult to accurately analyze the tumor specific T cells to assess the cytokine or phenotypic profiles that are associated with gain or loss of anti-tumor immune responses. To address these issues, this application proposes to create transgenic mice that develop mammary tumors that mimic human breast carcinoma in their progression and histologic characteristics. In addition, these tumors will express well characterized viral antigens from murine lymphocytic choriomeningitis virus, nucleoprotein (NP) and glycoprotein (GP) for use as model tumor antigens. Identification and sorting of naturally occurring T cells expressing T cell receptor (TCR) specific for such tumor antigens is made possible by the newly established technique of producing recombinant, tetrameric MHC class I and II proteins containing antigenic peptide that are able to bind to antigen specific T cells. These will allow for precise characterization of tumor specific T cells with regards to their surface phenotype, cytokine profiles, and activation or anergic state during emergence of endogenously produced mammary tumors and following various immunologic interventions. These studies will provide a clearer picture of CD4+ and CD8+ T cell anti-tumor immunity and better direct efforts at tumor immunotherapy in human patients.